Hypothalamic Surgery Research Articles

Chapter 7 - Posterior hypothalamus as a target in the treatment of aggression: From lesioning to deep brain stimulation

Intermittent explosive disorder can be described as a severe "affective aggression" condition, for which drugs and other supportive therapies are not fully effective. In the first half of the 19th century, experimental studies progressively increased knowledge of aggressive disorders. A neurobiologic approach revealed the posterior hypothalamic region as a key structure for the modulation of aggression. In the 1960s, patients with severe aggressive disorder, frequently associated with intellectual disability, were treated by bilateral stereotactic lesioning of the posterior hypothalamic area, with efficacy. This therapy was later abandoned because of issues related to the misuse of psychosurgery. In the last 2 decades, however, the same diencephalic target has been selected for the reversible treatment by deep brain stimulation, with success. This chapter presents a comprehensive approach to posterior hypothalamic surgery for the treatment of severely aggressive patients and discusses the experimental steps that allowed this surgical target to be selected. Surgical experiences are reported, together with considerations on target features and related encephalic circuits.

Adipsic diabetes insipidus in adult patients.

Adipsic diabetes insipidus (ADI) is a very rare disorder, characterized by hypotonic polyuria due to arginine vasopressin (AVP) deficiency and failure to generate the sensation of thirst in response to hypernatraemia. As the sensation of thirst is the key homeostatic mechanism that prevents hypernatraemic dehydration in patients with untreated diabetes insipidus (DI), adipsia leads to failure to respond to aquaresis with appropriate fluid intake. This predisposes to the development of significant hypernatraemia, which is the typical biochemical manifestation of adipsic DI. A literature search was performed to review the background, etiology, management and associated complications of this rare condition. ADI has been reported to occur in association with clipping of an anterior communicating artery aneurysm following subarachnoid haemorrhage, major hypothalamic surgery, traumatic brain injury and toluene exposure among other conditions. Management is very difficult and patients are prone to marked changes in plasma sodium concentration, in particular to the development of severe hypernatraemia. Associated hypothalamic disorders, such as severe obesity, sleep apnoea and thermoregulatory disorders are often observed in patients with ADI. The management of ADI is challenging and is associated with significant morbidity and mortality. Prognosis is variable; hypothalamic complications lead to early death in some patients, but recent reports highlight the possibility of recovery of thirst.

Severe Hypernatremia From a Urea-Induced Diuresis due to Body Protein Wasting in an Insulin-Resistant Type 2 Diabetic Patient

Hypernatremia is encountered after pituitary or hypothalamic surgery and typically is secondary to vasopressin deficiency resulting in increased free water clearance with inadequate water replacement. We report a type 2 diabetic patient with severe hypernatremia (Na⁺ = 161 mEq/L) after hypothalamic surgery. Unexpectedly, this was accompanied by persistent urinary hypertonicity and negative total but positive electrolyte free water clearance. Measurement of urinary electrolytes and urea revealed that an osmotic diuresis induced by urea derived principally by breakdown of endogenous protein was causative. Body protein losses over 48 hours were estimated to exceed 2 kg of lean mass. High-dose glucocorticoid, insulin resistance, and a postsurgical catabolic stress likely contributed. In surgically severely stressed individuals, proteolysis of endogenous protein can strongly impact body water metabolism and contribute to severe hypernatremia.

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Hypothalamic leptin gene therapy normalizes the mosaic skeletal phenotype of leptin-deficient ob/ob mice. However, it is not clear whether increased hypothalamic leptin alters bone metabolism in animals already producing the hormone. The objective of this study was to evaluate the long duration effects of recombinant adeno-associated virus-rat leptin (rAAV-Lep) hypothalamic gene therapy on weight gain and bone metabolism in growing and skeletally mature leptin-replete female Sprague-Dawley rats. Rats were either unoperated or implanted with cannulas in the third ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained on standard rat chow fed ad libitum for either 5 or 10 weeks (starting at 3 months of age) or 18 weeks (starting at 9 months of age). Tibias, femurs, or lumbar vertebrae were analyzed by micro-computed tomography and/or histomorphometry. In comparison with age-matched rAAV-GFP rats, rAAV-Lep rats maintained a lower body weight for the duration of studies. At 5 weeks after vector administration, rAAV-Lep rats had lower cancellous bone volume and bone marrow adiposity but higher osteoblast perimeter compared with nonoperated controls. However, these values did not differ between the two groups at 10 weeks after vector administration. Differences in cancellous bone volume and architecture were not detected between the rAAV-Lep and rAAV-GFP groups at either time point. Also, rAAV-Lep had no negative effects on bone in the 9-month-old skeletally mature rats at 18 weeks after vector administration. We hypothesize that the transient reductions in bone mass and bone marrow adiposity at 5 weeks after vector administration were due to hypothalamic surgery. We conclude that increased hypothalamic leptin, sufficient to prevent weight gain, has minimal specific effects (rAAV-Lep versus rAAV-GFP) on bone metabolism in normal female rats.

Syndrome of alternating hypernatremia and hyponatremia after hypothalamic hamartoma surgery

In this paper, the authors' goal was to describe the occurrence of alternating hypernatremia and hyponatremia in pediatric patients who underwent resection of hypothalamic hamartomas (HHs) for epilepsy. Hypernatremia in patients after pituitary or hypothalamic surgery can be caused by diabetes insipidus (DI), whereas hyponatremia can occur due to a syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, or excessive administration of desmopressin (DDAVP). The triphasic response after surgery in the pituitary region can also explain variations in sodium parameters in such cases. One hundred fifty-three patients with HH who underwent surgery were enrolled in a prospective study to monitor outcomes. Of these, 4 patients (2.6%) were noted to experience dramatic alterations in serum sodium values. The medical records of these patients were identified and evaluated. Patients' ages at surgery ranged from 1.2 to 6.0 years. All patients were girls. Two patients had Delalande Type IV lesions (of 16 total Type IV lesions surgically treated) and 2 had Type III lesions (of 39 total Type III lesions). All patients had a history of gelastic seizures refractory to medication. Seizure frequency ranged from 3 to 300 per day. After surgery, all patients experienced hypernatremia and hyponatremia. The largest fluctuation in serum sodium concentration during hospitalization in a single patient was 53 mEq/L (range 123-176 mEq/L). The mean absolute difference in maximum and minimum sodium values was 38.2 mEq/L. All patients exhibited an initial period of immediate DI (independent of treatment) after surgery followed by a period of hyponatremia (independent of treatment), with a minimum value occurring between postoperative Days 5 and 8. All patients then returned to a hypernatremic state of DI, and 3 patients still require DDAVP for DI management. A second occurrence of hyponatremia lasting several days without DDAVP administration occurred in 2 patients during their hospitalization between periods of hypernatremia. One patient stabilized in the normal range of sodium values prior to discharge from rehabilitation without the need for further intervention. At last follow-up, 3 patients are seizure-free. Severe instability of sodium homeostasis with hypernatremia and hyponatremia is seen in up to 2.6% of children undergoing open resection of HH. This risk appears to be related to HH type, with a higher risk for Types III (2 [5.1%] of 39) and IV (2 [12.5%] of 16) lesions. Here, the authors describe alternating episodes of hypernatremia and hyponatremia in the postoperative period following HH surgery. Management of this entity requires careful serial assessment of volume status and urine concentration and will often require alternating salt replacement therapy with DDAVP administration.

A case of central diabetes insipidus following probable type A/H1N1 influenza infection

The major causes of central diabetes insipidus (CDI) are neoplastic or infiltrative lesions of the hypothalamus or pituitary gland, severe head injuries, or pituitary or hypothalamic surgery. Lymphocytic infundibuloneurophysitis (LINH) is associated with autoimmune inflammatory disease of the pituitary gland, but the exact etiology is unknown. CDI caused by viral infections has been rarely reported. Here, we describe the case of a 22-year-old man who was in good health until 2 months prior to admission, presented with acute development of polyuria and polydipsia, and showed increased urinary volume up to 9000 mL/day. The patient showed elevated serum osmolality and low urine osmolality, with a low level of antidiuretic hormone. Endocrinological findings revealed CDI, but his arterial pituitary function appeared normal. Magnetic resonance imaging revealed significant enlargement of the pituitary stalk. We suspected CDI due to LINH based on non-transsphenoidal biopsy findings. He was diagnosed as type A influenza,and given oral therapeutic agents. However, acute onset of polyuria and polydipsia occurred 10 days after the influenza diagnosis. The available epidemiological information regarding the outbreak of influenza around that time strongly suggested that the patient was infected with the A/H1N1 influenza virus, although this virus had not been detected on polymerase chain reaction testing. In the present case, the autoimmune mechanism of LINH may have been associated with novel influenza A/H1N1 virus infection.

Hemodynamic changes after hypothalamic and brain stem surgery: interdisciplinary approach to studying

We discuss prognostic criteria of hemodynamic changes in patients after hypothalamic and brain stem surgery. We hope that better understanding of mechanisms of adaptive disorders in local brain lesions will help to optimize postoperative management of these patients. This study was based on the interdisciplinary neurocardiologic approach [1].

Diabetes Insipidus Due to Herpes Encephalitis in a Patient with Diffuse Large Cell Lymphoma. A Case Report

The major causes of central diabetes insipidus are neoplastic or infiltrative lesions of the hypothalamus or pituitary, severe head injuries and pituitary or hypothalamic surgery. Central diabetes insipidus caused by viral infections has been rarely reported in immunosuppressed patients, such as those with acquired immunodeficiency syndrome or Cushing's syndrome. We report the case of a 48-year-old woman suffering from diffuse large cell lymphoma, who developed hypotonic polyuria, hypernatriaemia and somnolence after the first course of chemotherapy with CHOEP and rituximab. Diabetes insipidus was diagnosed by low urine osmolarity and an undetectable vasopressin concentration. MRI revealed no pituitary abnormalities but encephalitis, and lumbar punction confirmed herpes zoster infection. To the best of our knowledge this is the first description of central diabetes insipidus in a lymphoma patient caused by an opportunistic CNS-infection.

Regulation of pituitary corticotropin releasing hormone (CRH) receptor mRNA and CRH binding during adrenalectomy: role of glucocorticoids and hypothalamic factors.

The role of glucocorticoids and hypothalamic factors on CRH receptor expression in the pituitary were studied by analysis of the effects of adrenalectomy and suppression of CRH and VP secretion by hypothalamic lesions in the rat. Consistent with previous in situ hybridization studies, Northern blots showed that pituitary CRH receptor mRNA decreased only transiently after adrenalectomy, falling to 51% of the control levels after 18 h, and returning to control values after 6 days (112%). The early decrease was prevented by dexamethasone injection, 100 micrograms, s.c. The role of increased levels of CRH and VP in the pituitary portal circulation on the transient decrease in CRH receptor mRNA levels after adrenalectomy were studied by in situ hybridization in rats subjected in PVN lesions or median eminence deafferentation by hypothalamic anterolateral cuts (ALC). PVN lesion (12 days) or ALC (8 days) resulted in undetectable irCRH and VP in the external zone of the median eminence and had no effect on basal levels of pituitary POMC mRNA, CRH binding and CRH receptor mRNA. In sham lesioned rats, adrenalectomy for 18 h or 4 days caused the expected increases in pituitary POMC hnRNA and mRNA, and decreases in CRH binding. CRH-R mRNA levels decreased by about 50% after 18 h adrenalectomy but returned to basal by 4 days. PVN lesion or ALC fully prevented the fall in CRH binding after 18 h or 4 days adrenalectomy and the increase in POMC mRNA after 4 days adrenalectomy, whereas only attenuated the decrease in CRH receptor mRNA and increase in POMC mRNA levels after 18 h adrenalectomy. Administration of a CRH antagonist did not affect CRH receptor mRNA and POMC hnRNA and mRNA indicating that residual CRH in the median eminence after hypothalamic surgery is not responsible for the effect of adrenalectomy. These studies confirm previous in situ hybridization studies showing that adrenalectomy causes transient decreases in pituitary CRH receptor mRNA levels. The data indicate that while increases in hypothalamic CRH secretion following glucocorticoid withdrawal mediate pituitary CRH receptor binding loss and the increase in POMC expression after long-term adrenalectomy, CRH only partially accounts for the early changes in CRH receptor mRNA and POMC mRNA.

Serum leptin levels following hypothalamic surgery.

To study a potential alteration of hypothalamic centers involved in the negative feedback action of leptin on body weight, serum leptin levels were measured in relation to BMI in 18 patients following surgery for a hypothalamic craniopharyngioma (Ctx), and were compared to levels found in 21 patients operated for a pituitary adenoma (Ptx) or in healthy control subjects. All subjects with Ptx received rhGH replacement therapy (0.5 to 2 IU/m2/d), and serum leptin levels were followed in 3 months intervals over 24 months. Serum leptin levels in patients with Ptx were comparable to controls, whereas 7 of the 18 patients with Ctx had higher than expected concentrations for their BMI. GH treatment in Ptx subjects did not alter serum leptin levels. In 5 Ctx patients where preoperative samples were available, weight gain in parallel to an increase in serum leptin levels was observed but only minimal changes in 4 others. Our data support the role of leptin as an important marker of body weight. The rapid increase in serum leptin levels observed in some Ctx subjects suggests that early postoperative measurement of serum leptin levels may help to identify patients at risk of weight gain following hypothalamic destruction.

Potential for fertility with replacement of hypothalamic gonadotropin-releasing hormone in long term female survivors of cranial tumors.

Dysfunction of the hypothalamic-pituitary axis presenting as hypogonadotropic amenorrhea is a common sequelae of treatment for cranial tumors with surgery and/or radiation. We hypothesized that the site of the defect in this condition is hypothalamic, rather than pituitary, in the majority of patients. Nine women with acquired hypogonadotropic hypogonadism after treatment with transphenoidal pituitary surgery (n = 3), transphenoidal surgery plus conventional radiotherapy (XRT; n = 1), hypothalamic surgery plus XRT (n = 2), or XRT with or without noncentral nervous system surgery (n = 3) underwent assessment of endogenous pulsatile LH secretion and a standard GnRH test followed by iv administration of a physiological replacement regimen of exogenous GnRH. A total of 25 cycles were completed at doses of 75 or 100 ng/kg.bolus. Ovulation occurred in 78% of patients, with all ovulatory patients who desired fertility becoming pregnant. The hormonal responses in these cycles did not differ from the patterns of sex steroids and gonadotropins in normal women. The response to pulsatile GnRH was not influenced by GH deficiency or PRL abnormalities. Of the two patients who failed to ovulate, there was no evidence of folliculogenesis in one, whereas the second consistently developed follicles, but proved incapable of mounting a LH surge despite adequate preovulatory estradiol levels. Both patients had a history of pituitary radiation and surgery. There was no consistent relationship between the results of GnRH testing and the pattern of pulsatile LH secretion. However, the only patient who failed to achieve folliculogenesis was the only patient without a FSH response to GnRH testing and an apulsatile baseline study. Hypothalamic GnRH deficiency is the etiology of hypogonadism in the majority of patients after treatment with hypothalamic or pituitary surgery or cranial irradiation. Therefore, exogenous pulsatile GnRH represents a physiological replacement therapy that completely restores normal gonadotropin dynamics, resulting in ovulation and fertility.

Vasopressin antagonist in early postoperative diabetes insipidus

23 patients without diabetes insipidus before transfrontal (hypothalamic) or trans-sphenoidal (pituitary) surgery were studied prospectively to investigate the pathogenesis of early postoperative diabetes insipidus. 12 patients who underwent trans-sphenoidal surgery and who did not develop diabetes insipidus were used as controls. All received prophylactic corticosteroid replacement. Blood samples were obtained immediately after operation, at the onset of diabetes insipidus, and 24 h later. Immediately after trans-sphenoidal pituitary surgery, plasma vasopressin (AVP) was raised but had fallen to subnormal concentrations by the onset of diabetes insipidus. After transfrontal hypothalamic surgery diabetes insipidus occurred sooner and was associated with high plasma AVP immunoreactivity—but the plasma showed no antidiuretic bioactivity and greatly attenuated the antidiuretic response to standard AVP. Early diabetes insipidus after hypothalamic surgery is associated with release of a substance, presumably an analogue, from the damaged hypothalamo-neurohypophyseal system, which acts as an antagonist to normal AVP activity; after trans-sphenoidal operations diabetes insipidus seems to be caused by failure of AVP release.

Effect of intermittent infusions of somatostatin on growth hormone secretion in unrestrained male rats with hypothalamic deafferentation

The effect of intermittent infusions of somatostatin (SS) on growth hormone (GH) secretion was studied in unrestrained adult male rats deprived largely of SS influence on the medial basal hypothalamus by anterolateral deafferentation (AL-cut). In addition, the influence of hypothalamic surgery on the plasma GH response to β-endorphin (β-END) was observed. In sham-operated rats, high-amplitude GH pulses separated by low baseline levels occurred at 185 min intervals. In rats with AL-cut, GH pulses were difficult to identify upon visual appraisal and baseline plasma GH levels became significantly higher than those of sham-operated rats. When AL-cut was performed unilaterally (half-AL-cut), low amplitude GH pulses separated by elevated baseline GH levels occurred at frequent intervals. The amount of GH secreted during 6 h was significantly reduced in rats with AL-cut or half-AL-cut as compared to that of sham-operated rats. The plasma GH response to intracerebroventricular injection of β-END (4 μg) was abolished in AL-cut rats, and the response was significantly reduced in half-AL-cut rats as compared to that of sham-operated rats. When AL-cut rats were subjected to repeated infusions of SS (30 μg/kg b. wt./h, 150 min) separated by 30 min control periods, a large rebound of GH secretion was observed after removal and the amount of GH secreted during 6 h became comparable to that of sham-operated rats. The results suggest that SS plays important roles in the dynamic secretion of GH.

Hypophysiotrophic function of vasopressin and oxytocin

We have investigated the effects of lesioning the hypothalamic paraventricular nucleus (PVN) on the secretion of two corticotropin-releasing neurohormones, vasopressin (VP) and oxytocin (OT), at the median eminence. The experimental model was the median eminence incubated in vitro, the secretion of neurohormones was stimulated by adding 48 mM KCl to the incubation medium. In addition, immunohistochemical staining was performed to correlate the changes in neuropeptide secretion with the distribution of VP and OT immunoreactive elements in the median eminence. Lesioning of the PVN abolished the KCl-induced release of VP 1 week after hypothalamic surgery. After a longer period of postoperative survival (6 weeks), VP release was restored towards normal. The secretion of OT was reduced by 50% at 1 week after lesioning and rose to 400% of control at six weeks. The changes in VP and OT release at the median eminence largely correlated with the immunohistochemical distribution of VP and OT immunopositive nerve fibers in the external zone of the median eminence. Most importantly, 6 weeks after the PVN lesion a dense network of OT immunoreactive varicosities was observed around primary portal capillaries, where normally OT fiber density is very low. These results demonstrate the functional and structural plasticity of VP- and OT-ergic neuronal systems that project to the median eminence. Furthermore, when taken together with earlier studies on the regulation of corticotropin secretion in long-term PVN-lesioned rats, the data indicate an important role for OT in the regulation of pituitary-adrenocortical function in PVN-lesioned rats.

Selective osmoreceptor dysfunction presenting as intermittent hypernatremia following surgery for a pituitary chromophobe adenoma

Intermittent hypematremia following hypothalamic surgery or trauma is usually attributed to the triphasic dysfunction of vasopressin release (diabetes insipidus, inappropriate vasopressin release, and diabetes insipidus). A 39-year-old patient had hypodipsia and intermittent hypematremia following hypothalamic surgery for a chromophobe adenoma. Mean arterial pressure fell by 25 percent during orthostasis testing and was associated with an increase in vasopressin levels from 1.3 μU/ml to 12 μU/ml. Plasma renin activity and aldosterone increased from 1.1 to 16 ng/ml per hour and from 6.7 to 39 ng/dl, respectively, and remained elevated for three and a half hours after tilt testing. Hypertonic saline infusion, on the other hand, increased serum osmolality from 290 to 304 mOsm/kg but did not result in a significant rise in vasopressin levels (all were less than 1 μU/ml). These results are consistent with a selective dysfunction of the osmoreceptor pathways of vasopressin release and intact volume receptor-mediated pathways. Patients with intermittent hypematremia following hypothalamic surgery or trauma should be questioned specifically regarding thirst. If it is impaired or absent, these patients should be watched carefully, not only for the development of triphasic dysfunction of vasopressin release, but also for a selective osmoreceptor dysfunction associated with thirst deficits as found in patients with “essential hypernatremia.”

Pituitary binding of vasopressin is altered by experimental manipulations of the hypothalamo-pituitary-adrenocortical axis in normal as well as homozygous (di/di) Brattleboro rats.

In the present study we report the properties of vasopressin (VP) receptors in the anterior pituitary gland and show that the number of these receptors is markedly affected by adrenalectomy and hypothalamic lesions. VP-binding activity was assayed in particulate fractions of rat anterior pituitary glands using tritium-labeled arginine VP ([3H] AVP) as tracer. In the presence of Mg2+ the radioligand interacted with a single class of high affinity, low capacity binding sites. Magnesium ions modulated the affinity of the receptors but had no effect on binding capacity. Guanine nucleotides decreased the amount of tracer bound in a dose-dependent manner by increasing the dissociation constant (Kd) of the binding reaction by approximately 2-fold. Increasing the concentration of Mg2+ did not prevent this effect. Bilateral adrenalectomy (ADX) decreased pituitary AVP-binding activity: binding fell by 30% 4 h after surgery and declined further to 10% or less of control at 4 days. The decrease in binding was primarily due to a reduction in the number of receptors. Daily administration of corticosterone inhibited the reduction of binding activity at 4 days in a dose-dependent manner. Destruction of hypophyseotropic VP neurons by means of surgical lesioning of the hypothalamic paraventricular nucleus or the medial basal hypothalamus abolished the effect of ADX on pituitary AVP binding at 24 h but only attenuated the degree of receptor loss at 4 days. Furthermore, the lesions themselves caused a significant (approximately 30%) reduction in receptor number 4-7 days after hypothalamic surgery. Adrenalectomy reduced pituitary AVP-binding activity in homozygous (di/di) Brattleboro rats. The extent as well as the time course of the loss of receptor activity resembled that in normal rats. Rat anterior pituitary segments were exposed to synthetic CRF, AVP, or oxytocin (all 10(-7) M) for 4 h in vitro, and [3H] AVP-binding activity was subsequently determined. Both AVP and oxytocin reduced the amount of radioligand bound, while CRF had no effect. These observations allow the following conclusions: Magnesium ions and guanine nucleotides modulate the affinity of pituitary AVP receptors by different mechanisms and have no effect on binding capacity; Pituitary receptors for AVP are regulated by the amount of AVP released by paraventricular nucleus neurons as well as through a mechanism that requires the presence of corticosterone; Homozygous Brattleboro rats may respond to ADX by increased hypothalamic release of an endogenous ligand for pituitary AVP receptors.

7 Somatomedin activity in disorders of nutrition and metabolism

The existence of the somatomedin peptides was originally hypothesized to explain questions based on studies of growth hormone (GH) action (Salmon and Daughaday, 1957). The demonstration of serum factors which appeared GH-responsive and stimulated growing cartilage in vitro provided evidence for such mediators of GH effects. Subsequent measurements of somatomedins in disorders of the GH axis (GH deficiencyacromegaly) further supported the hypothesis by showing a general correlation with circulating levels of GH. However, extension of somatomedin measurements to other conditions suggested that somatomedins might be regulated by other mechanisms as well. Situations of 'no growth despite GH' and 'growth without GH' were found in which circulating somatomedins or somatomedin activity appeared to parallel levels of insulin and nutritional status more closely than levels of GH (Table 1). Thus, in kwashiorkor and diabetes, growth may be poor despite normal to elevated levels of GH (Hansen and Johansen, 1970; Grant et al, 1973); in these conditions, low levels of somatomedin activity appear to parallel insulin and nutrition more than GH. Conversely, children who are obese or who have had hypothalamic surgery may grow well despite low levels of GH (Van den Brande and Du Caju, 1974; Costin et al, 1976); in such conditions, normal levels of somatomedin activity again appear to parallel levels of insulin and nutrition more than levels of GH. In combination, such observations indicate that somatomedins -- and growth -- are modulated by insulin and nutrition as well as by GH. In view of the anabolic insulin-like actions of the somatomedin peptides (Phillips and Vassilopoulou-Sellin, 1980), such non-GH regulation suggests that somatomedin mechanisms may play an important role in diverting calorie use toward or away from 'growth' as a reflection of nutritional/ hormonal status. While a number of tissues appear to be able to generate somatomedins de novo under tissue culture conditions, the best evidence to date indicates that non-GH regulation of circulating somatomedin activity occurs in the liver.

Hypothalamic hyperphagia and obesity in rats with jejunoileal bypass

Jejunoileal bypass or sham surgery was performed in adult female rats followed 35 days later by ventromedial hypothalamic (VMH) knife cut or sham surgery (forming groups Bypass-VMH, Bypass-Sham, Sham-VMH, and Sham-Sham). Bypassed rats receiving VMH cuts (Bypass-VMH group) ate more food and gained more weight than did either Bypass-Sham or Sham-Sham groups. The hyperphagia and obesity of the Bypass-VMH rats was, however, substantially less than that of the sham bypass VMH cut rats (Sham-VMH group). Bypass-VMH rats that had their intestinal tract reconnected increased their food intake and ultimately became as obese as the Sham-VMH rats. Two additional groups received VMH knife cut or sham surgery followed 50 days later by jejunoileal bypass surgery (VMH-Bypass and Sham-Bypass groups). At the time of the bypass the VMH-Bypass group was hyperphagic and obese, but after surgery they underate and lost weight until they eventually stabilized their body weight at a level below that of the Sham-Bypass group. The body weight of the VMH-Bypass group was also 167 g less than that of the Bypass-VMH group. Thus, the order of surgery significantly influences the food intake and body weight level of rats with VMH knife cuts and jejunoileal bypass.

Food intake and body weight following jejunoileal bypass in obese and lean rats

The effects of jejunoileal bypass (JIB) surgery on food intake and body weight were investigated in obese and lean rats. Obese rats lost considerably more weight after bypass surgery than did lean animals, and reduced food intake was the primary cause of their weight loss. Both the degree and type of obesity influenced the anorexia and weight reduction produced by JIB. Hypothalamic obesity was completely reversed by JIB, but genetic obesity (fatty rat) and spontaneous obesity were only partially blocked. However, JIB performed prior to hypothalamic surgery attenuated, but did not prevent the development of hyperphagia and obesity. The weight loss produced by JIB was fully recovered following reconnection of the intestinal tract. The feeding and weight reducing effects of JIB appear to result, at least in part, from the visceral malaise produced by the surgery, and from feeding inhibitory signals produced by overstimulation of the lower ileum.

A stereotaxic x-ray map of the hypothalamus of the marmoset monkey Callithrix jacchus.

Precise hypothalamic surgery in the marmoset monkey Callithrix jacchus cannot be performed by means of the Horsley-Clarke stereotaxic procedure. Thus, a simple stereotaxic X-ray technique was developed. Technical requirements are a stereotaxic frame for small animals and a dental X-ray source. A sagittal map shows hypothalamic structures in relation to surrounding bony landmarks. Corresponding coronal plates allow target determination in that plane. Intracerebral coordinates based on the position of the optic chiasma can be transformed into individual Horsley-Clarke coordinates. The error of the atlas is estimated as +/- 0.25 mm anteroposteriorly, +/- 0.1 mm coronally, and +/- 0.5 mm vertically.